Indeed, the LBD of VDR is able to physically interact with the NACHT-LRR domain of NLRP3 thus inhibiting the association of NLRP3 with BRCC3 and preventing NLRP3 deubiquitination (XREF_FIG).

For instance, ubiquitination of NLRP3 by FBXL12, TRIM1, ARIH2 or the dopamine-induced E3 ligase MARCH7 promotes the proteasomal degradation of NLRP3 in resting macrophages ( xref ), whereas deubiquitylation of NLRP3 LRR domain on K63 by BRCC3 triggers ASC oligomerization and inflammasome activation ( xref , xref ) ( xref ).

For instance, ubiquitination of NLRP3 by FBXL12, TRIM1, ARIH2 or the dopamine induced E3 ligase MARCH7 promotes the proteasomal degradation of NLRP3 in resting macrophages, whereas deubiquitylation of NLRP3 LRR domain on K63 by BRCC3 triggers ASC oligomerization and inflammasome activation (XREF_FIG).

Together these data indicate that PPARgamma and Rev-erbalpha may inhibit NK-kappaB-dependent NLRP3 priming (XREF_FIG).

Indeed, while low extracellular Cl - enhances ATP induced IL-1beta secretion, high extracellular Cl - concentration or Cl - channel blockers inhibit NLRP3 activation.

For instance, ubiquitination of NLRP3 by FBXL12, TRIM1, ARIH2 or the dopamine induced E3 ligase MARCH7 promotes the proteasomal degradation of NLRP3 in resting macrophages, whereas deubiquitylation of NLRP3 LRR domain on K63 by BRCC3 triggers ASC oligomerization and inflammasome activation (XREF_FIG).

Interestingly, the bile acid receptor FXR is also able to physically interact with NLRP3 and Caspase1 thus inhibiting NLRP3 activity (XREF_FIG).

Furthermore, vitamin D enhances VDR mediated inhibition of NLRP3 activation.

Particularly, VDR has been shown to prevent NLRP3 modification on K63 and its subsequent activation.

Furthermore, vitamin D enhances VDR mediated inhibition of NLRP3 activation.

Since ROS scavengers attenuate NLRP3 activation, the generation of ROS was considered a common cellular response critical for NLRP3 activation.

In addition to caspase 1, cytosolic gram negative bacteria derived LPS may also be sensed independently of TLR4 signaling by human caspases 4 and 5, and mouse caspase 11, to induce the non canonical NLRP3 inflammasome.

In human hepatic hepG2 cell line, palmitic acid and LPS co-treatment induces the expression of NLRP3, NLRP6 and NLRP10 as well as Caspase 1 and IL-1beta.

In human hepatic hepG2 cell line, palmitic acid and LPS co-treatment induces the expression of NLRP3, NLRP6 and NLRP10 as well as Caspase 1 and IL-1beta.

For instance, ubiquitination of NLRP3 by FBXL12, TRIM1, ARIH2 or the dopamine induced E3 ligase MARCH7 promotes the proteasomal degradation of NLRP3 in resting macrophages, whereas deubiquitylation of NLRP3 LRR domain on K63 by BRCC3 triggers ASC oligomerization and inflammasome activation (XREF_FIG).

In addition, NLRP3 may also interact with mitochondrial antiviral signaling protein (MAVS), which is another mitochondrial outer MAM.

In addition, NLRP3 may also interact with mitochondrial antiviral-signaling protein (MAVS), which is another mitochondrial outer MAM ( xref – xref ).

Indeed, the LBD of VDR is able to physically interact with the NACHT-LRR domain of NLRP3 thus inhibiting the association of NLRP3 with BRCC3 and preventing NLRP3 deubiquitination ( xref ) ( xref ).

In addition, mtROS promotes Thioredoxin-interacting protein (TXNIP)-NLRP3 interaction involved in NLRP3 expression ( xref ) ( xref ).

Upon stimulation, NLRP3 oligomerizes through homotypic interactions between NACHT domains of two NLRP3 proteins and the subsequent recruitment of ASC through PYD-PYD interactions ( xref ).

For instance, the NLRP3 and Caspase1 complex is able to cleave GR, thus impairing glucocorticoid activity in acute lymphoblastic leukemia (ALL) patients.

In addition, vitD3 dampens ASC speck formation by preventing the NLRP3 and NEK7 interaction.

Regulation of NEK7-NLRP3 assembly is induced by ATP-driven potassium efflux ( xref ) but also in a K + -efflux independent manner ( xref ) and by reactive oxygen species (ROS) production ( xref ).

Interestingly, in addition to LPS, the pro atherogenic apolipoprotein ApoC3 is able to trigger TLR2 and TLR4 heterodimerization and promotes the alternative activation of NLRP3, thus mirroring the effect of oxLDL in the canonical activation of NLRP3.

Then, the ASC adaptor accumulates at Mitochondria associated ER membranes (MAMs) where the NLRP3 and ACS complex is formed.

Then, the ASC adaptor accumulates at Mitochondria-associated ER membranes (MAMs) where the NLRP3-ACS complex is formed ( xref ).

However, as HIF1alpha induces NLRP3 inflammasome activation, such regulatory mechanism may then account for LXR dependent activation of IL1-beta production in hypoxic atherosclerotic lesions.

Strikingly, ERbeta inhibits TNFalpha driven apoptosis and activates NLRP3 in endometriotic tissues.

Strikingly, ERβ inhibits TNFα-driven apoptosis and activates NLRP3 in endometriotic tissues ( xref ).

Remarkably, inhibition of the NLRP3 inflammasome pathway reduces liver inflammation and fibrosis in an experimental mouse NASH model.

Intriguingly, Berberine inhibits NLRP3 activation in DSS induced colitis in a Rev-erbalpha-dependent manner.

Although the source of NLRP3 activating ROS was controversial, the inhibition of the lysosomal NADPH oxidase did not alter NLRP3 activation in mouse and human cells, thus suggesting an alternative source of NLRP3 activating ROS, likely the mitochondria.

Interestingly, human LPS primed macrophages treated with ATRA exhibit elevated NLRP3 RNA and protein levels associated with an increase in caspase 1 and pro-IL-1beta maturation.

This signaling pathway relies on a cascade involving TLR4, TIR domain containing adapter molecule 1 (TRIF), RIPK1, FADD and caspase 8 that finally promotes NLRP3 activation.

The priming step has two main purposes : the transcriptional induction of the inflammasome complex components NLRP3, Caspase 1, IL-1beta, and IL-18 and the induction of post-translational modifications of NLRP3 (XREF_FIG).

Two recent reports demonstrated that chloride intracellular channels (CLICs), especially CLIC1 and CLIC4 mediate NLRP3 activation by promoting Cl - efflux downstream nigericin induced K + efflux and mitochondrial ROS production, which promotes CLIC translocation to the plasma membrane (XREF_FIG).

Indeed, treatment of BMDM with bile acids suppresses LPS and Nigericin mediated NLRP3 activation in a TGR5-cAMP-PKA dependent by inducing NLRP3 ubiquitination and phosphorylation.

Accordingly, aldosterone induced renal tubular cell injury by activating NLRP3 in a mtROS dependent manner.

Epleronone abolishes aldosterone induced NLRP3, ASC, Casp1, and IL-18 maturation in mouse kidney, but the mechanism is still uncovered.

In this context, aldosterone promotes mtROS production and subsequent NLRP3 activation.

Altogether, VDR inhibits NLRP3 inflammasome by favoring NLRP3 ubiquitination, preventing NLRP3 assembly and reducing ROS mediated NLRP3 activation.

Nevertheless, RORgamma deletion in LPS primed BMDM inhibits NLRP3 and IL-1beta secretion, which is consistent with a RORgamma inhibiting effect of SR1555 and SR2211 on these processes.

Here, we demonstrate that epidermal growth factor receptor (EGFR) activation induces AKT dependent PCK1 pS90, PCK1 mediated INSIG1 pS207 and INSIG2 pS151, and nuclear SREBP1 accumulation in NSCLC cells.

Lapatinib, the small molecule tyrosine kinase inhibitor which targets HER2 and EGFR, has considerable anti-tumor activity against HER2+ BC cells, including trastuzumab resistant cells.

Given the fact that Lapatinib is a dual EGFR and HER2 inhibitor, we chose the HER2 overexpressing BC cell line, HCC-1954, and the EGFR overexpressing benign control cell line, MCF-10A, for further evaluation.

As we discussed, the PTM of the EZH2-ubiquitination pathway is an important negative regulator of EZH2.

For instance, CDK1-mediated pT345-EZH2 and pT487-EZH2 facilitate EZH2 ubiquitination degradation in breast cancer cell, cervical cancer cell and lung cancer cell [ xref , xref , xref ]; JAK2 phosphorylates Y641-EZH2, leading to E3 ligase β-TrCP-mediated EZH2 degradation in lymphoma cell [ xref ]; and CDK5 phosphorylation of EZH2 at T261 residue results in the E3 ubiquitin ligase FBW7-mediated degradation of EZH2 in pancreatic cancer cell [ xref ].

Mechanistically, YC-1 treatment promotes c-Cbl phosphorylation at T731 and T774, which results in c-Cbl-induced Src and ERK activation, leading to the formation of the c-Cbl-ERK-EZH2 complex and the consequent accumulation of EZH2 ubiquitination and proteasomal degradation.

The first research of EZH2 ubiquitination was from the Aaron lab’s work in 2011 [ xref ].

Ubiquitination, sumoylation, and deubiquitination of EZH2 in tumorigenesis and cancer metastasis.

We showed that R342-EZH2 methylation inhibits TRAF6-mediated EZH2 ubiquitination [ xref ].

Another recent study has reported that CDK5-mediated T261-EZH2 phosphorylation facilitates FBW7-mediated EZH2 ubiquitination and proteasome degradation in pancreatic cancer cells [ xref ].

They found that pT345-EZH2 and pT487-EZH2 facilitate EZH2 ubiquitination and hence its degradation by the proteasome pathway in human cervical cancer cells [ xref ].

Our recent study has also confirmed that CDK1-mediated pT345-EZH2 and pT487-EZH2 facilitate EZH2 ubiquitination and subsequent degradation in breast cancer [ xref ].

Moreover, a recent report has revealed that SYDM2 catalyzes EZH2-K307 di-methylation attenuating EZH2-ubiquitination degradation in breast cancer [ xref ].

OGT-mediated O -GlcNAcylation of EZH2 attenuates EZH2 ubiquitination in breast cancer cell [ xref , xref ]; PCAF-mediated EZH2-K348 acetylation inhibits CDK1 catalyzing pT345-EZH2 and pT487-EZH2 and increases EZH2 stability in lung cancer [ xref ].

SETD2-mediated mono-methylation of EZH2-K735 promotes EZH2 ubiquitination in prostate cancer [ xref ].

They confirmed that circ-ADD3 binding with EZH2 facilitates CDK1-mediated EZH2 phosphorylation on T345 and T487, which results in EZH2 ubiquitination degradation in HCC cells.

Sun et al. found that circ-ADD3, as a circular RNA, inhibits hepatocellular carcinoma (HCC) metastasis through facilitating EZH2 degradation through CDK1-mediated EZH2 ubiquitination [ xref ].

Subsequently, the researchers designed a highly specific NEK2 inhibitor, CMP3a, which can promote EZH2 ubiquitination degradation and inhibit GBM tumor growth.

Mechanically, they elucidated that YC-1 facilitates E3-ligase c-Cbl phosphorylation at T731 and T774, leading to the activation of c-Cbl and complex formation with EZH2, and then EZH2 ubiquitination degradation.

A series of small molecules have been shown to facilitate EZH2-ubiquitination degradation.

Moreover, researchers demonstrated that E3 ligase CHIP can mediate EZH2 ubiquitination degradation and subsequently derepress EZH2-silenced tumor suppressor genes by attenuating the H3K27me3 level in head and neck cancer cells [ xref ].

Ubiquitination, sumoylation, and deubiquitination of EZH2 in tumorigenesis and cancer metastasis.

A study showed that sumoylation of EZH2 is associated with EZH2 activity in U2OS cell (osteosarcoma cell line) [ xref ].

Moreover, another study demonstrated that JAK3-mediated EZH2 tyrosine (Y) Y244 phosphorylation, which suppresses PRC2 complex formation, resulting in EZH2 oncogenic function independent of its HMTase activity in natural killer/T-cell lymphoma (NKTL) [ xref ].

In addition, p38 catalyzing EZH2 phosphorylation at T367 residue elevates its localized to cytoplasm and promotes breast cancer cells distant metastasis [ xref ].

In addition, our recently studies discovered that PRMT1-mediated EZH2-R342 methylation attenuates CDK1-mediated EZH2-T345 and EZH2-T487 phosphorylation, which strengthens EZH2 stability [ xref , xref ].

They confirmed that circ-ADD3 binding with EZH2 facilitates CDK1-mediated EZH2 phosphorylation on T345 and T487, which results in EZH2 ubiquitination degradation in HCC cells.

Our recent research has illustrated that ANCR, a type of lncRNAs, promotes EZH2-T345 phosphorylation by associating with EZH2 [ xref ].

For instance, CDK1-mediated pT345-EZH2 and pT487-EZH2 facilitate EZH2 ubiquitination degradation in breast cancer cell, cervical cancer cell and lung cancer cell [ xref , xref , xref ]; JAK2 phosphorylates Y641-EZH2, leading to E3 ligase β-TrCP-mediated EZH2 degradation in lymphoma cell [ xref ]; and CDK5 phosphorylation of EZH2 at T261 residue results in the E3 ubiquitin ligase FBW7-mediated degradation of EZH2 in pancreatic cancer cell [ xref ].

For instance, CDK1 mediated pT345-EZH2 and pT487-EZH2 facilitate EZH2 ubiquitination degradation in breast cancer cell, cervical cancer cell and lung cancer cell [XREF_BIBR, XREF_BIBR, XREF_BIBR]; JAK2 phosphorylates Y641-EZH2, leading to E3 ligase beta-TrCP-mediated EZH2 degradation in lymphoma cell [XREF_BIBR]; and CDK5 phosphorylation of EZH2 at T261 residue results in the E3 ubiquitin ligase FBW7 mediated degradation of EZH2 in pancreatic cancer cell [XREF_BIBR].

Talha et al. [ xref ] revealed that p38 phosphorylated EZH2 at T367 site facilitating its cytoplasmic localization and interacting with vinculin and other cytoskeletal regulators of cell migration and invasion.

In 2018, Li et al. [ xref ] demonstrated that AMPK phosphorylates EZH2 at T311 residue to inhibit EZH2 binding with SUZ12, thereby attenuating the PRC2-dependent methylation of H3K27 and enhancing PRC2 target genes translation in ovarian and breast cancers.

In 2018, Li et al. [XREF_BIBR] demonstrated that AMPK phosphorylates EZH2 at T311 residue to inhibit EZH2 binding with SUZ12, thereby attenuating the PRC2 dependent methylation of H3K27 and enhancing PRC2 target genes translation in ovarian and breast cancers.

As early as 2005, Cha et al. [XREF_BIBR] showed phosphorylation of EZH2 at S21 (pS21-EZH2) by PI3K and AKT signaling in breast cancer cells.

SETD2-mediated mono-methylation of EZH2-K735 promotes EZH2 ubiquitination in prostate cancer [ xref ].

Furthermore, Kim et al. [ xref ] found that AKT-induced pS21-EZH2 elevates EZH2-mediated STAT3 methylation by increasing EZH2-STAT3 interaction in glioblastoma multiforme (GBM) stem-like cells.

In 2020, Yuan et al. [ xref ] reported that SETD2 methylates EZH2 at K735 promoting EZH2 degradation and impeding prostate cancer metastasis.

In 2020, Yuan et al. [XREF_BIBR] reported that SETD2 methylates EZH2 at K735 promoting EZH2 degradation and impeding prostate cancer metastasis.

A study demonstrated that the phosphorylation of EZH2 at Y646 residue in human (Y641 in mouse) by JAK2 promotes the beta-TrCP-mediated EZH2 degradation and consequent regulation of H3K27me3 [XREF_BIBR].

AKT-mediated pS21-EZH2 inhibits its methyltransferase activity by attenuating EZH2 associated with histone H3, which attenuates H3K27me3 level, increases EZH2 target genes expression, and facilitates breast cancer tumorigenesis.

Moreover , Jin et al. [ 50 ] revealed that FBW7 decreases EZH2 activity and attenuates the motility of pancreatic cancer cells by mediating the degradation of the EZH2 ubiquitin proteasome pathway .

Moreover, Jin et al. [XREF_BIBR] revealed that FBW7 decreases EZH2 activity and attenuates the motility of pancreatic cancer cells by mediating the degradation of the EZH2 ubiquitin proteasome pathway.

Recently , a report has confirmed that Praja1 degrades EZH2 during skeletal myogenesis [ 38 ] .

Aaron and his colleagues illustrated that Praja1 promotes EZH2 degradation through K48-linkage polyubiquitination and suppresses cells growth and migration in breast cancer [ 87 ] .

Silvia et al. [XREF_BIBR] revealed that p38alpha promotes E3 ligase Praja1 mediated EZH2 degradation through the phosphorylation of T372-EZH2 (T367-EZH2 in mouse).

This finding disclosed that Praja1 mediated EZH2 degradation is required for muscle satellite cells differentiation.

Recently, a report has confirmed that Praja1 degrades EZH2 during skeletal myogenesis [XREF_BIBR].

Aaron and his colleagues illustrated that Praja1 promotes EZH2 degradation through K48-linkage polyubiquitination and suppresses cells growth and migration in breast cancer [XREF_BIBR].

They found that Ub E3 ligase Praja1 mediates EZH2 protein degradation through the ubiquitination-proteasome pathway in MCF7 cells (breast cancer cell line).

A recent research has disclosed that sorafenib can prevent EZH2 expression by accelerating its ubiquitination-proteasome degradation in hepatoma cells [ 117 ] .

Moreover, NSC745885, as a small molecular, is derived from natural anthraquinone emodin, which can downregulate EZH2 via proteasome mediated degradation [XREF_BIBR].

Besides, Ma and his colleagues found that Ubiquitin specific protease 1 (USP1) directly interacts with and deubiquitinates EZH2.

For instance, EZH2 can promote the invasion and metastasis by suppressing E-cadherin transcriptional expression [XREF_BIBR, XREF_BIBR]; EZH2 can also increase tumorigenesis by silencing tumor suppressors [XREF_BIBR, XREF_BIBR, XREF_BIBR].

Reports on AKT-mediated pS21-EZH2 support the presumption that pS21-EZH2 mediated by AKT results in EZH2 promoting oncogenesis by several novel functions, which is independent on PRC2-mediated target gene transcriptional silencing.

Interestingly, arsenic-induced pS21-EZH2 is mainly cytoplasmic localization.

Instead of transcriptional repression EZH2 target gene expression, pS21-EZH2 serves as a transcriptional co-activator in castration-resistant prostate cancer through PI3K/AKT signaling [ xref ].

AKT-mediated pS21-EZH2 inhibits its methyltransferase activity by attenuating EZH2 associated with histone H3, which attenuates H3K27me3 level, increases EZH2 target genes expression, and facilitates breast cancer tumorigenesis.

As early as 2005, Cha et al. [ xref ] showed phosphorylation of EZH2 at S21 (pS21-EZH2) by PI3K/AKT signaling in breast cancer cells.

For instance, AKT-mediated pS21-EZH2 can promote breast cancer tumorigenesis [ xref , xref ].

They confirmed that the OGT-EZH2 axis inhibits tumor suppression by repressing the expression of several key tumor suppression genes in breast carcinoma.

They demonstrated that ZRANB1 can bind, deubiquitinate, and stabilize EZH2, which enhances breast cancer tumorigenesis and metastasis.

They demonstrated that ZRANB1 can bind, deubiquitinate, and stabilize EZH2, which enhances breast cancer tumorigenesis and metastasis.

We disclosed that ANCR-EZH2 interaction enhances CDK1 binding with EZH2 and increases the amount of pT345-EZH2, which results in EZH2 degradation and subsequently suppressing the oncogenesis and distant metastasis in breast cancer.

We disclosed that ANCR-EZH2 interaction enhances CDK1 binding with EZH2 and increases the amount of pT345-EZH2, which results in EZH2 degradation and subsequently suppressing the oncogenesis and distant metastasis in breast cancer.

Although AKT-mediated-EZH2-S21 phosphorylation reduces its affinity toward histone H3, it does not change its subcellular localization or its interaction with Polycomb group protein SUZ12 and EED subunits.

A study revealed that Smurf2 can interact with EZH2 and mediate EZH2 ubiquitination-proteasome degradation.

A study revealed that Smurf2 can interact with EZH2 and mediate EZH2 ubiquitination-proteasome degradation.

We speculate that ANCR-EZH2 association may change the conformation of EZH2, which probably facilitates the recognition and binding of CDK1 on EZH2 to phosphorylate its T345 residue.

We disclosed that ANCR-EZH2 interaction enhances CDK1 binding with EZH2 and increases the amount of pT345-EZH2, which results in EZH2 degradation and subsequently suppressing the oncogenesis and distant metastasis in breast cancer.

Furthermore, Kim et al. [ xref ] found that AKT-induced pS21-EZH2 elevates EZH2-mediated STAT3 methylation by increasing EZH2-STAT3 interaction in glioblastoma multiforme (GBM) stem-like cells.

It means that OGT mediated EZH2 GlcNAcylation have several different functions in breast cancer progression.Acetylation is a reversible and important PTM that regulates a series of cellular processes, including proliferation, apoptosis, migration, and metabolism, in cancer cells; it is achieved through the modulation of core histones or non histone proteins by histone acetyltransferases (HATs) or histone deacetylases (HDACs) [XREF_BIBR - XREF_BIBR].

This report also found that OGT mediated O GlcNAcylation at S75 stabilizes EZH2 and subsequently facilitates the formation of H3K27me3 on PRC2 target genes.

Professor Wong 's team first provided convincing evidence on OGT mediated EZH2 O GlcNAcylation at S75 in breast cancer [XREF_BIBR].

It means that EZH2 can activate gene expression and oncogenesis without being dependent on its methyltransferase activity .

For instance , EZH2 can promote the invasion and metastasis by suppressing E-cadherin transcriptional expression [ 28 , 29 ] ; EZH2 can also increase tumorigenesis by silencing tumor suppressors [ 9 , 20 , 25 ] .

For instance , EZH2 can promote the invasion and metastasis by suppressing E-cadherin transcriptional expression [ 28 , 29 ] ; EZH2 can also increase tumorigenesis by silencing tumor suppressors [ 9 , 20 , 25 ] .

EZH2 reportedly promotes cancer development and metastasis [ 9 , 17 , 18 ] .

They demonstrated that ZRANB1 can bind , deubiquitinate , and stabilize EZH2 , which enhances breast cancer tumorigenesis and metastasis .

EZH2 reportedly promotes cancer development and metastasis [XREF_BIBR, XREF_BIBR, XREF_BIBR].

A series of studies demonstrated that EZH2 can promote cancer tumorigenesis and metastasis independent on PRC2 mediated target gene silencing.

In addition, p38 catalyzing EZH2 phosphorylation at T367 residue elevates its localized to cytoplasm and promotes breast cancer cells distant metastasis [XREF_BIBR].

This finding suggests that EZH2 can promote breast cancer metastasis through novel functions in cytoplasm.

For instance , EZH2 can promote the invasion and metastasis by suppressing E-cadherin transcriptional expression [ 28 , 29 ] ; EZH2 can also increase tumorigenesis by silencing tumor suppressors [ 9 , 20 , 25 ] .

A study reported that YC-1 decreases EZH2 expression and inhibits breast cancer cell proliferation via activation of its ubiquitination and proteasome degradation [XREF_BIBR].

They also disclosed that pT350-EZH2 can elevate EZH2 mediated cell proliferation and migration.

Recently, Wan et al. [ xref ] have elucidated that EZH2-K348 residue is acetylated by acetyltransferase P300/CBP-associated factor (PCAF) and is deacetylated by deacetylase SIRT1 in lung cancer cells.

Moreover, PCAF acetylates EZH2 at the K348 site promoting lung cancer tumorigenesis via stabilizing EZH2 [XREF_BIBR].

H3K27me3 and EZH2 are involved in inhibiting and maintaining the low-level and stable state of fibrosis and inflammation genes in mesangial cells, while H3K27me3 and EZH2 are inhibited by TGF-β, which increases the expression of genes that mediate glomerular mesangial dysfunction and DN, leading to renal dysfunction ( xref ).

In vitro and in vivo studies confirmed that the abnormal increase of EZH2 can inhibit the expression level of E-cadherin, induce the epithelial stromal transformation of renal cancer cells, and promote the occurrence, development and recurrence of renal cancer.

EZH1 and EZH2 are the core components of PRC2, while EED can interact with EZH1 or EZH2 to maintain enzyme activity.

Studies have demonstrated that EZH2 can promote the development and metastasis of RCC.

Thus, inhibition of EZH2 can reduce the survival and invasion of clear cell renal cell carcinoma (ccRCC) cells and the growth of ccRCC in xenografted mice.

EZH2 also has growth promoting activity in RCC and can enhance the proliferation and invasion of renal tubular epithelial cells.

EZH2 inhibition elicits an anti-EMT effect related to preservation of E-cadherin expression, repression of transcription factors (i.e., Snail, twist), and deactivation of PTEN and Akt and beta-catenin signaling pathways.

EZH2 inhibition elicits an anti-EMT effect related to preservation of E-cadherin expression, repression of transcription factors (i.e., Snail, twist), and deactivation of PTEN and Akt and beta-catenin signaling pathways.

EZH2 also has growth promoting activity in RCC and can enhance the proliferation and invasion of renal tubular epithelial cells.

Moreover, EZH2 promotes cell proliferation, migration and angiogenesis by inhibiting expression of tumor suppressor genes such as p27Kip1 and enhancing expression of proto-oncogenes.

Blocking EZH2 by 3-DZNep and GSK126 can effectively inhibit the adhesion of lupus T cells to human microvascular endothelial cells.

In the same injury model, EZH2 inhibition also reduced renal dysfunction and tubular injury by regulating p38 signaling, apoptosis and inflammation.

In a murine model of cisplatin induced-AKI, inhibition of EZH2 expression by 3-DZNep could also reduce apoptosis of renal tubular cells and ameliorate acute renal injury by restoring expression of E-cadherin.

In the same injury model, EZH2 inhibition also reduced renal dysfunction and tubular injury by regulating p38 signaling, apoptosis and inflammation.

EZH2 inhibition elicits an anti-EMT effect related to preservation of E-cadherin expression, repression of transcription factors (i.e., Snail, twist), and deactivation of PTEN and Akt and beta-catenin signaling pathways.

Moreover, EZH2 promotes cell proliferation, migration and angiogenesis by inhibiting expression of tumor suppressor genes such as p27Kip1 and enhancing expression of proto-oncogenes.

In the same injury model, EZH2 inhibition also reduced renal dysfunction and tubular injury by regulating p38 signaling, apoptosis and inflammation.

EZH2 can also stimulate the expression of T cell multifunctional cytokines by activating the Notch pathway, and promoting T cell survival by Bcl-2 expression.

Emerging evidence has shown the role of EZH2 mediated histone modifications in AKI.

EZH2 inhibition elicits an anti-EMT effect related to preservation of E-cadherin expression, repression of transcription factors (i.e., Snail, twist), and deactivation of PTEN and Akt and beta-catenin signaling pathways.

For the degradation of EZH2, JAK2 phosphorylates EZH2 at tyrosine 641 [ xref ].

For the degradation of EZH2, JAK2 phosphorylates EZH2 at tyrosine 641 [XREF_BIBR].

Phosphorylation of EZH2 on serine 21 by protein kinase B (AKT) inhibits PRC2-mediated H3K27 enzymatic activity.

Based on these expression patterns and enhanced uterine epithelial proliferation in these mice, it was postulated that EZH2 suppresses differentiation of basal like cells and consequently restricts uncontrolled uterine epithelial proliferation.

Based on these expression patterns and enhanced uterine epithelial proliferation in these mice, it was postulated that EZH2 suppresses differentiation of basal like cells and consequently restricts uncontrolled uterine epithelial proliferation.

Whether EZH2 acts to repress or stimulate transcription largely relates to its association with other proteins .

Whether EZH2 acts to repress or stimulate transcription largely relates to its association with other proteins.

The interaction of EZH2 with ANGPTL4 [ xref ] was reported in human cytotrophoblasts.

For example, the transcription factor Yin Yang 1 (YY1) directly interacts with EZH2 and recruits it to specific genome sites to regulate gene expression.

Both EZH2 and YY1 are associated with repressing tumor suppressor APC in endometrioid endometrial carcinomas [ xref ].

In addition to determining that EZH2 promotes trophoblast invasion in JAR cells, the authors also found that EZH2 represses a tumor repressor gene that inhibits EMT, caudal type homeobox 1 (CDX1) [XREF_BIBR].

For example, EZH2 functions as a co-activator of estrogen receptor 1 (ESR1; also known as ERa) and promotes the transcription of its target genes.

Increased Expression of EZH2 Is Mediated by Higher Glycolysis and mTORC1 Activation in Lupus CD4 + T Cells.

Increased Expression of EZH2 Is Mediated by Higher Glycolysis and mTORC1 Activation in Lupus CD4

In summary, our findings suggest that EZH2 overexpression in SLE CD4 + T cells is induced by mTORC1 activation and increased glycolysis through effects on post-transcriptional regulation by miR-26a and miR-101 (XREF_FIG).

Increased Expression of EZH2 Is Mediated by Higher Glycolysis and mTORC1 Activation in Lupus CD4 + T Cells.

Indeed, inhibiting mTORC1 increased miR-26a and miR-101 and suppressed EZH2 expression in SLE CD4 + T cells.

Increased Expression of EZH2 Is Mediated by Higher Glycolysis and mTORC1 Activation in Lupus CD4

There are three potential mechanisms to explain these paradoxical findings : ( 1 ) Oxidative stress can induce EZH2 expression by additional mechanisms independent of our suggested mTORC1 / glycolysis / miRNA axis ; ( 2 ) A negative feedback homeostasis loop may exist to suppress EZH2 via miR-26a and miR-101 as EZH2 levels were significantly increased about 40 folds with oxidative stress ; and ( 3 ) miR-26a and miR-101 could be directly regulated by oxidative stress independent of mTORC1 / glycolysis .

These results suggest that oxidative stress upregulated EZH2 expression , via mechanisms that might be independent of post-transcriptional regulation by miR-26a and miR-101 .

This is consistent with EZH2 mediated epigenetic changes in naive CD4 + T cells that were previously observed when SLE becomes more active [XREF_BIBR].

EZH2 mediates abnormal CD4 + T cells adhesion in SLE by epigenetic dysregulation of the junctional adhesion molecule A (JAM-A) [XREF_BIBR].

The mechanisms underlying EZH2 upregulation in SLE CD4 + T cells remain unknown.

Increased disease activity in SLE patients is associated with a proinflammatory epigenetic shift in naive CD4 + T cells, likely mediated by EZH2.

EZH2 mediates abnormal CD4 + T cells adhesion in SLE by epigenetic dysregulation of the junctional adhesion molecule A (JAM-A) [XREF_BIBR].

In summary, our findings suggest that EZH2 overexpression in SLE CD4 + T cells is induced by mTORC1 activation and increased glycolysis through effects on post-transcriptional regulation by miR-26a and miR-101 (XREF_FIG).

Increased EZH2 is mediated by activation of mTORC1 and increased glycolysis in SLE CD4 + T cells.

Increased EZH2 is mediated by activation of mTORC1 and increased glycolysis in SLE CD4 + T cells .

Conclusion : Increased EZH2 is mediated by activation of mTORC1 and increased glycolysis in SLE CD4 + T cells .

Because mTORC1 is activated in SLE CD4 + T cells in part due to increased oxidative stress , and mTORC1 activation increases glycolysis , we hypothesized that mTORC1 mediates increased EZH2 expression .

Taken together, these data suggest that increased mTORC1 activity in SLE CD4 + T cells might mediate upregulation of EZH2 through increasing glycolysis and the resulting suppression of miR-26a and miR-101.

Because mTORC1 is activated in SLE CD4 + T cells in part due to increased oxidative stress , and mTORC1 activation increases glycolysis , we hypothesized that mTORC1 mediates increased EZH2 expression .

Increased EZH2 is mediated by activation of mTORC1 and increased glycolysis in SLE CD4 + T cells.

Specifically, in acute myeloid leukemia (AML), both the RUNX1-RUNX1T1 fusion and the CBFB-MYH11 subtypes have lower levels of OGG1 expression, which correlate with increased therapeutic-induced cell cytotoxicity and good prognosis for improved, relapse-free survival compared with other AML patients.

Specifically, in acute myeloid leukemia (AML), both the RUNX1-RUNX1T1 fusion and the CBFB-MYH11 subtypes have lower levels of OGG1 expression, which correlate with increased therapeutic-induced cell cytotoxicity and good prognosis for improved, relapse-free survival compared with other AML patients.

Further, NF-kB inhibition by overexpression of IkB also results in S15 phosphorylation of mutant p53 via GADD45α mediated JNK1 activation ( xref ).

Chronic S15 phosphorylation of mutant p53 has been found in tumors where DNA damage signaling is constitutively activated ( xref , xref ).

On the contrary , Nanog suppresses p53 activity while Gli activated by Nanog inhibits p53 by activating Mdm2 to promote pluripotency .

For example , p53 repress CD133 by directly binding to its promoter and recruiting HDAC1 ( Figure 2 ) .

p53 loss upregulates CD133 which subsequently promotes CSC marker expression and confers stemness .

Furthermore, p53 loss was found to trigger dedifferentiation of mature hepatocytes to pluripotent cells by the activation of SC marker Nestin, which remains suppressed in wild-type p53 bearing cells (XREF_FIG).

With the advent of reprogramming era, it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions.

TP53 maintains homeostasis between self-renewal and differentiation depending on the cellular and developmental state and prevents the dedifferentiation and reprogramming of somatic cells to stem cells.

Loss or gain-of-function mutations in TP53 induce dedifferentiation and proliferation of SCs with damaged DNA leading to the generation of CSCs.

With the advent of reprogramming era , it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions .

Association of p53 inactivation and loss of differentiation characteristics has also been reported in AML and lung cancer (XREF_FIG).

Also , upon DNA damage , p53 primarily promotes differentiation by suppression of Nanog .

Mutant p53 mediated repression of p63 function can also modulate the expression of certain miRNAs involved in invasion and metastasis such as let-7i, miR-155, miR-205, miR-130b, and miR-27a (XREF_FIG).

Mutant p53 can itself disrupt the balance between stem cell proliferation and differentiation as well as sequester p63 or p73 thereby hindering apoptosis, augmenting proliferation, and driving chemoresistance and metastasis typical of cancer stem cells.

Hence, loss of NUMB in breast cancer cells leads to decreased p53 levels and increased activity of NOTCH receptor which confers increased chemoresistance.

It may form a complex with mutant p53 and MDM2 to block their ubiquitination mediated degradation or may form a complex with mutant p53 to prevent aggregation of mutant p53 by inhibiting MDM2 and CHIP in multiple cancer cell lines ( xref , xref ).